Dr. Andrea Schietinger is a motivated basic research scientist with a strong background in tumor immunology. Dr. Schietinger's immediate goals are to understand the regulatory mechanism(s) of T cell unresponsiveness in self-antigen and tumor-antigen specific CD8 T cells and evaluate strategies to override T cell-intrinsic tolerance programs to improve cancer immunotherapy. Dr. Schietinger will use clinically relevant mouse models to elucidate the precise molecular and epigenetic programs underlying T cell tolerance to self-antigens (K99 award period). Insights gained from the self-tolerance model will then be applied to a newly developed autochthonous solid cancer model to understand why tumor-specific T cells in premalignant lesions and/or early tumors become unresponsive to the cancer (R00 award period). The Specific Aims are: (1) To define the self-tolerant T cell epigenome through comprehensive, high-resolution genome-wide analysis of chromatin states and to determine how tolerance memory is encoded, (2) To evaluate the functional characteristics of tumor-induced T cell dysfunction and to determine if functional unresponsiveness of tumor-specific T cells is an imprinted differentiation state similar to self-tolerance, and (3) To evaluate strategies to erase the epigenetic memory in dysfunctional tolerant T cells and to permanently rescue T cell function for cancer immunotherapy. Elucidating the genetic and epigenetic regulatory mechanism(s) of T cell unresponsiveness in different settings such as self-tolerance and tumor- induced T cell tolerance may reveal common underlying principles of T cell dysfunction and lead to new therapeutic approaches for cancer and other T cell-mediated diseases such as autoimmunity and chronic infections. Dr. Schietinger will carry out the research during the mentored K99 award period under the guidance of Dr. Philip Greenberg, Professor in the Department of Immunology, University of Washington, and Head of the Program of Immunology, Fred Hutchinson Cancer Research Center (FHCRC). Dr. Greenberg is a leading researcher in the field of mouse and human tumor immunology with a proven track record of successful mentorship. The University of Washington (UW) and (FHCRC) provide an excellent environment with the necessary resources, including infrastructure, personnel, instrumentation and core facilities, to carry out the proposed studies. Dr. Schietinger has formed an excellent scientific advisory committee that assures her academic progress and will complement Dr. Greenberg's mentorship. The committee members include Drs. Michael Bevan, Professor in the Department of Immunology (UW); John Stamatoyannopulos, Professor in the Department of Genome Sciences (UW); and Members of the FHCRC including Drs. Stanley Riddell, Program of Immunology, Muneesh Tewari, Human Biology and Clinical Research Division, and Kim Margolin, Professor of Medicine (UW) and Head of the Melanoma Clinic at the Seattle Cancer Care Alliance. All of these members are experts in their fields and will bring additional insights and technologies to her project in the areas of T cell biology and T cell memory, epigenetics, microRNA, and clinical/human tumor immunology. In the long-term, Dr. Schietinger's goal is to become a tumor immunologist with an independent research program using mouse models to decipher the complex interplay between cancer cells and immune cells in solid tumors and find opportunities to use the acquired insights to develop better treatments for human cancers.